UNLABELLED: Gastrin-releasing peptide (GRP) receptors have been shown to be expressed with high densities on several types of cancer cells including prostate, breast, small cell lung, and pancreas cancers. Bombesin (BBN) has been known to bind to GRP receptors with high affinity and specificity. The aim of these studies was to develop new (111)In-labeled BBN analogs having high tumor uptake and optimal pharmacokinetics for specific targeting of human prostate cancers. METHODS: A novel series of dodecanetetraacetic acid (DOTA)-X-BBN[7-14]NH(2) (X = 0, beta-Ala, 5-Ava, 8-Aoc, or 11-Aun) conjugates and their In(III)/(111)In complexes exhibiting high GRP-receptor-binding affinities were synthesized and characterized. RESULTS: In vitro competitive binding assays, using PC-3 androgen-independent human prostate cancer cells, demonstrated values of <2.5 nmol/L for inhibitory concentration of 50% for analogs with beta-Ala, 5-Ava, and 8-Aoc spacers. In vivo biodistribution studies of the (111)In-DOTA-X-BBN[7-14]NH(2) conjugates performed on CF-1 mice at 1 h after injection have revealed that the uptake of radioactivity in the pancreas, a GRP-receptor-expressing tissue, increased as a function of hydrocarbon spacer length (i.e., from 0.20 +/- 0.04 percentage injected dose [%ID] per gram for the analog with no spacer to a maximum of 26.97 +/- 3.97 %ID/g for the analog with 8-Aoc spacer). The radioactivity was cleared efficiently from the blood pool by excretion mainly through the renal/urinary pathway (e.g., 71.6 +/- 1.8 %ID at 1 h after injection for 8-Aoc spacer analog). In vivo pharmacokinetic studies of the (111)In-DOTA-8-Aoc-BBN[7-14]NH(2) conjugate conducted on PC-3 human prostate cancer-derived xenografts in SCID mice showed a specific uptake of radioactivity in tumor, with 3.63 +/- 1.11 %ID/g observed at 1 h after injection. High tumor-to-blood and tumor-to-muscle ratios of approximately 6:1 and 45:1, respectively, were achieved at 1 h after injection. Relative to the radioactivity observed in the tumor at 1 h after injection, 43%, 19%, and 9% of the radioactivity was retained at, respectively, 24, 48, and 72 h after injection. CONCLUSION: These studies showed that radiometallated DOTA-X-BBN[7-14]NH(2) constructs with hydrocarbon spacers ranging from 5 to 8 carbon atoms are feasible candidates for further development as diagnostic and therapeutic radiopharmaceuticals for patients with GRP-positive cancers.
UNLABELLED: Gastrin-releasing peptide (GRP) receptors have been shown to be expressed with high densities on several types of cancer cells including prostate, breast, small cell lung, and pancreas cancers. Bombesin (BBN) has been known to bind to GRP receptors with high affinity and specificity. The aim of these studies was to develop new (111)In-labeled BBN analogs having high tumor uptake and optimal pharmacokinetics for specific targeting of humanprostate cancers. METHODS: A novel series of dodecanetetraacetic acid (DOTA)-X-BBN[7-14]NH(2) (X = 0, beta-Ala, 5-Ava, 8-Aoc, or 11-Aun) conjugates and their In(III)/(111)In complexes exhibiting high GRP-receptor-binding affinities were synthesized and characterized. RESULTS: In vitro competitive binding assays, using PC-3 androgen-independent humanprostate cancer cells, demonstrated values of <2.5 nmol/L for inhibitory concentration of 50% for analogs with beta-Ala, 5-Ava, and 8-Aoc spacers. In vivo biodistribution studies of the (111)In-DOTA-X-BBN[7-14]NH(2) conjugates performed on CF-1 mice at 1 h after injection have revealed that the uptake of radioactivity in the pancreas, a GRP-receptor-expressing tissue, increased as a function of hydrocarbon spacer length (i.e., from 0.20 +/- 0.04 percentage injected dose [%ID] per gram for the analog with no spacer to a maximum of 26.97 +/- 3.97 %ID/g for the analog with 8-Aoc spacer). The radioactivity was cleared efficiently from the blood pool by excretion mainly through the renal/urinary pathway (e.g., 71.6 +/- 1.8 %ID at 1 h after injection for 8-Aoc spacer analog). In vivo pharmacokinetic studies of the (111)In-DOTA-8-Aoc-BBN[7-14]NH(2) conjugate conducted on PC-3 humanprostate cancer-derived xenografts in SCIDmice showed a specific uptake of radioactivity in tumor, with 3.63 +/- 1.11 %ID/g observed at 1 h after injection. High tumor-to-blood and tumor-to-muscle ratios of approximately 6:1 and 45:1, respectively, were achieved at 1 h after injection. Relative to the radioactivity observed in the tumor at 1 h after injection, 43%, 19%, and 9% of the radioactivity was retained at, respectively, 24, 48, and 72 h after injection. CONCLUSION: These studies showed that radiometallated DOTA-X-BBN[7-14]NH(2) constructs with hydrocarbon spacers ranging from 5 to 8 carbon atoms are feasible candidates for further development as diagnostic and therapeutic radiopharmaceuticals for patients with GRP-positive cancers.
Authors: Dijie Liu; Douglas Overbey; Lisa D Watkinson; Charles J Smith; Said Daibes-Figueroa; Timothy J Hoffman; Leonard R Forte; Wynn A Volkert; Michael F Giblin Journal: Bioconjug Chem Date: 2010-07-21 Impact factor: 4.774
Authors: Christopher T Winkelmann; Said Daibes Figueroa; Gary L Sieckman; Tammy L Rold; Timothy J Hoffman Journal: Mol Imaging Biol Date: 2012-12 Impact factor: 3.488
Authors: Wael R Abd-Elgaliel; Fabio Gallazzi; Jered C Garrison; Tammy L Rold; Gary L Sieckman; Said Daibes Figueroa; Timothy J Hoffman; Susan Z Lever Journal: Bioconjug Chem Date: 2008-09-23 Impact factor: 4.774
Authors: Dustin Wayne Demoin; Ashley N Dame; William D Minard; Fabio Gallazzi; Gary L Seickman; Tammy L Rold; Nicole Bernskoetter; Michael E Fassbender; Timothy J Hoffman; Carol A Deakyne; Silvia S Jurisson Journal: Nucl Med Biol Date: 2016-08-31 Impact factor: 2.408